During the menopause transition, many women report a worsening of their mood and a subjective impairment in memory. While dwindling ovarian production of estrogen is clearly related to the most common menopausal symptoms, namely hot flashes and genitourinary atrophy, the mechanism by which estrogen may influence behavioral changes during menopause is unclear, although of great interest. A growing preclinical literature indicates that estrogen interactions with neurotransmitters such as serotonin are likely, and serotonin function is believed to decline with age. However, there is a dearth of research in humans regarding how estrogen and serotonin may interact to modulate mood and cognition. Our group has recently made strides to fill this void by demonstrating that estrogen treatment (ET) modulates verbal memory performance in menopausal women undergoing depletion of tryptophan (TRP), the precursor of serotonin (Amin et al. 2006b;Epperson et al. 2006). Compared to sham depletion, tryptophan depletion (TRP-D) prior to ET worsened verbal recall, while no such effect was seen after 10-12 weeks of ET. These preliminary findings suggest that ET may protect individuals from deficits in verbal recall due to selective reduction in serotonin. The present application seeks to determine the individual and interactive effects of estrogen and serotonin on cognitive and affective processing and brain activation through the addition of functional magnetic resonance imaging (fMRI) to the paradigm of TRP-D before and during ET or placebo treatment in menopausal women. In addition, funding for this study will enable us to recruit women at varying stages of the menopause to determine the interactive effects of duration of menopause and ET on outcomes of interest. This application is both novel and timely as results from this study are likely to provide information critical to the on-going discussion regarding the risks and benefits of ET use in menopausal women. PUBLIC HEALTH RELEVANCE: The overarching purpose of this study is to further our understanding of the individual and interactive effects of the hormone estrogen and the neurotransmitter serotonin on certain aspects of cognition and brain activation in menopausal women ages 48 to 60 years. Women will undergo cognitive testing and fMRI sessions both before and after 6 weeks of either estrogen or placebo administration. We will recruit women who are across the first 10 years since their last menstrual period so that we can gather information regarding the potential impact of time since menopause on our outcomes of interest. We anticipate that findings from this study will help scientist and clinicians to refine their use of estrogen therapy in menopausal women. In addition, should the role of serotonin be of utmost importance for maintenance of healthy cognition, these data aid future drug development to preserve health cognition and/or to treat dementias in which serotonin is an important factor. This application is both novel and timely as results from this study are likely to provide information critical to the on-going discussion regarding the risks and benefits of ET use in menopausal women.